Role of Insulin and Insulin-like Growth Factor Signaling in Obesity Associated Colorectal Cancer

 

Trainee:

Agostina Santoro

Santoro

Research Mentor:

Dr. P. Kay Lund, PhD

Lund

Clinical Co-mentor:

Dr. Michael Kappelman, MD, MPH

Kappelman

Clinical Co-mentor:

Dr. Robert Sandler, MD, MPH

Sandler
Home Department Physiology
Project Description

Obesity, insulin-resistance, and associated hyperinsulinemia increase risk of colorectal cancer (CRC). Elevated insulin increases bioavailable insulin-like growth factor I (IGF-I). Increased risk of colorectal adenoma in obesity and insulin resistance may therefore reflect anti-apoptotic or mitogenic actions of insulin and/or IGF-I acting on the insulin receptor (IR), the IGF-I receptor (IGF-IR), or both. IR exists as an IR-B isoform, which mediates metabolic effects of insulin, and an IR-A isoform, which is up-regulated in a number of cancers and implicated in cell growth. However, recent findings indicate that loss of IR facilitates anti-apoptotic effects of IGF-IR in colon cancer cells and demonstrate that insulin-sensitizing drugs such as metformin reduce colorectal cancer risk. These findings have prompted us to hypothesize that IGF-IR is the primary mediator of obesity-associated risk of CRC and that high relative levels of IR versus IGF-IR protect against colorectal neoplasia during obesity and hyperinsulinemia by limiting the ability of insulin or IGFs to activate the IGF-IR. Furthermore, we propose that metformin decreases risk of pre-cancerous adenoma in obese and diabetic patients by limiting the growth-promoting actions of IGF-IR and favoring IR action. We will use mouse models of obesity and CRC and human samples from colon biopsies to define whether increased IR-A or IR-B relative to IGF-IR decreases the risk of CRC during obesity or hyperinsulinemia. Epidemiological studies will be performed to determine how the insulin-sensitizing drug metformin reduces the risk of colorectal polyps using a database containing health insurance claims from 70 million patients across the U.S. A better fundamental understanding of the roles of IR versus IGF-IR in mediating adenoma or cancer risk associated with obesity and insulin resistance will guide optimization of strategies to improve prevention and treatment of colorectal neoplasia.